Synaptic mechanisms underlying noise-induced and age-related hearing loss

描述（由申请人提供）：噪声性听力损失（NIHL）和年龄相关性听力损失（阿勒）是两种主要的听力损伤，受影响的个体通常在处理声音的精细时间结构方面表现出受损的能力。虽然大多数NIHL和阿勒的研究都集中在外周缺陷，但对中枢听觉系统的伴随改变知之甚少。本研究旨在探讨Held突触内球处NIHL和阿勒后突触传递的变化及其细胞机制。这些突触是中枢听觉系统的第一个突触连接，并且众所周知在精细的时间处理中是重要的。初步数据表明，在小鼠endbulls的Held的突触传递与NIHL和阿勒受损，可能是由于受损的钙稳态endbulls终端。本建议的第一个目的是检验这一假设，即突触前末梢钙浓度的升高强调了NIHL后持续活动期间异常的突触释放。将在正常和NIHL小鼠中评价突触传递，其利用改变活性区附近的微区和纳米区中的钙缓冲的操作。通过评估突触传递同时破坏特定途径（包括通过电压门控钙通道的外部钙内流、Ca-钙调蛋白依赖性钙通道失活和通过兰尼碱受体和IP 3受体从内部钙储存中释放钙诱导的钙）来确定钙升高的来源。第二个目标是通过研究突触后丛状细胞的放电特性来探索NIHL后突触传递变化的功能影响。这一目的将检验NIHL小鼠中异步释放增加导致突触功效降低和时间精度受损的假设。特别是，该研究还将探索可以在切片中快速恢复灌木状细胞正常放电特性的操作。本研究的第三个目的是验证阿勒中终球突触传递受损与NIHL中观察到的钙稳态受损机制相同的假设。与目标1和2一样，目标3将检查阿勒老年小鼠的突触传递并测试信号传导通路。本研究的长期目标是确定NIHL和阿勒后中枢听觉系统突触修饰的共同细胞机制，并确定可以在临床前模型中急性挽救正常突触功能的操作。最终，这些研究可以为NIHL和阿勒的未来临床治疗提供方法。

DESCRIPTION (provided by applicant): Noise-induced hearing loss (NIHL) and age-related hearing loss (AHL) are two major hearing impairments, and affected individuals often show compromised ability in processing fine temporal structures of sound. While most studies of NIHL and AHL focus on the peripheral defects, much less is known about accompanying alterations in the central auditory system. This proposal will explore the changes of synaptic transmission and the underlying cellular mechanisms following NIHL and AHL at the endbulb of Held synapses. These synapses are the first synaptic connection of the central auditory system and are well known to be important in fine temporal processing. Preliminary data shows that synaptic transmission at mouse endbulbs of Held is compromised with NIHL and AHL, likely due to impaired calcium homeostasis in the endbulb terminals. The first aim of this proposal will test the hypothesis that elevation of calcium concentration at the presynaptic terminal underlines the aberrant synaptic release during sustained activity following NIHL. Synaptic transmission will be evaluated in both normal and NIHL mice utilizing manipulations that modify calcium buffering in the microdomain and nanodomains near the active zone. The source of the calcium elevation will be identified by assessing synaptic transmission while disrupting specific pathways including external calcium influx via voltage-gated calcium channels, Ca-calmodulin dependent calcium channel inactivation, and calcium induced calcium release from internal calcium stores via ryanodine receptors and IP3 receptors. The second aim of this proposal will explore the functional impact of the changes in synaptic transmission following NIHL by examining the firing properties of postsynaptic bushy cells. This aim will test the hypothesis that increase in asynchronous release in NIHL mice leads to decreased synaptic efficacy and compromised temporal precision. Particularly, the study will also explore manipulations that can acutely restore the normal firing properties of bushy cells in slice. The third aim of this proposal will tst the hypothesis that impaired synaptic transmission at the endbulbs during AHL share the same impaired calcium homeostasis mechanisms as observed in NIHL. As in Aims 1 and 2, Aim 3 will examine the synaptic transmission and test the signaling pathways in aged mice with AHL. The long-term goal of this study is to identify the common cellular mechanisms that underlie synaptic modifications of the central auditory system following NIHL and AHL, and to identify manipulations that can acutely rescue normal synaptic function in a preclinical model. Ultimately, these studies could suggest approaches for future clinical treatments of NIHL and AHL.